Recent developments in anti-angiogenic and vascular-disrupting therapies have shown the great potential of tumor vasculature as a therapeutic target for cancer medicine. We have an original idea for using targeted gold nanoparticles (GNP) as vascular disruptive agents (VDA) in conjunction with clinical megavoltage photon beams. Unlike competing proposals, we recognize that gold nanoparticles tend to accumulate in, and can even be targeted for, tumor blood vessels and that these structures may be more important for anti-cancer therapy than clonogenic cell death alone. Due to the short distance traveled by x-ray induced photoelectrons, the endothelial cells of the tumor will receive a sizable boost in dose, even for clinical megavoltage (MV) photon irradiation. Our preliminary results include: development, characterization and testing of a novel 4th generation nano-platform; theoretical and experimental evidence of dose enhancement in a MV clinical radiation therapy beam-line; and imaging studies of preferential tumor uptake. The proposed study will determine the optimal time window for radiation therapy after GNP administration and measure the therapy benefit in a preclinical lung cancer model. Our innovative therapy concept is highly compatible with current clinical practice and could offer a substantial clinical benefit with minimal patient risk.